The CD40/CD154 inflammatory axis has proven critical in autoimmune inflammation. Attempts to control it have used antibodies and synthesized organic small molecules; each ultimately has failed to be useful as a therapeutic. Controlling that axis with anti- CD154 proved highly effective, but the antibody itself caused lethal problems in human trials. We designed a small (15-mer) therapeutic peptide (STP) derived from the CD154 amino acid sequence that is known to interact with CD40. We determined that the STP binds directly to cell surface expressed CD40, particularly to CD40+ T cells, a subset that we described as highly pathogenic in the NOD mouse model of T1D, and in human T1D. Pre-diabetic human subjects have elevated levels of CD4+CD40+ cells that respond to human islets. Treating only T cells with the peptide ablates islet response. Administration of the peptid prevents hyperglycemia in 96% of treated NOD mice compared to a scrambled peptide or smaller versions of the peptide. Importantly the number of amino acids comprising the peptide is crucial for efficacy. In this application we will examine the mechanism of action of this peptide. Aim 1: Hypothesis: The STP has direct effects on pathogenic effector T cells, specifically CD4+CD40+ cells: Exploring the mechanism(s) of tolerance. Aim 2 will explore how the peptide affects the overall immune response including antigen recall, potential antibody production to foreign antigens and the possibility that peptide treatment induces antibodies to CD154. The ultimate goals of this research plan are to create a therapeutic to control pathogenic effector T cells.